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Nat Genet. 2018 Jul;50(7):1011-1020. doi: 10.1038/s41588-018-0140-x. Epub 2018 Jun 4.

The transcription factor Grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes.

Author information

1
VIB Center for Brain and Disease Research, Laboratory of Computational Biology, Leuven, Belgium.
2
KU Leuven, Department of Human Genetics, Leuven, Belgium.
3
VIB Center for Cancer Biology, Leuven, Belgium.
4
KU Leuven, Department of Oncology, Leuven, Belgium.
5
Bogazici University, Molecular Biology and Genetics, Istanbul, Turkey.
6
Politecnico di Torino, Automatics and Informatics, Turin, Italy.
7
VIB Center for Brain and Disease Research, Laboratory of Computational Biology, Leuven, Belgium. stein.aerts@kuleuven.vib.be.
8
KU Leuven, Department of Human Genetics, Leuven, Belgium. stein.aerts@kuleuven.vib.be.

Abstract

Transcriptional enhancers function as docking platforms for combinations of transcription factors (TFs) to control gene expression. How enhancer sequences determine nucleosome occupancy, TF recruitment and transcriptional activation in vivo remains unclear. Using ATAC-seq across a panel of Drosophila inbred strains, we found that SNPs affecting binding sites of the TF Grainy head (Grh) causally determine the accessibility of epithelial enhancers. We show that deletion and ectopic expression of Grh cause loss and gain of DNA accessibility, respectively. However, although Grh binding is necessary for enhancer accessibility, it is insufficient to activate enhancers. Finally, we show that human Grh homologs-GRHL1, GRHL2 and GRHL3-function similarly. We conclude that Grh binding is necessary and sufficient for the opening of epithelial enhancers but not for their activation. Our data support a model positing that complex spatiotemporal expression patterns are controlled by regulatory hierarchies in which pioneer factors, such as Grh, establish tissue-specific accessible chromatin landscapes upon which other factors can act.

PMID:
29867222
PMCID:
PMC6031307
DOI:
10.1038/s41588-018-0140-x
[Indexed for MEDLINE]
Free PMC Article

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